Cholecalciferol (vitamin D.sub.3) has been known to be intimately associated with bone metabolism and effectively used for the cure of rickets and osteomalacia since the early 1920s. Studies carried out during the last decade have shown that vitamin D.sub.3 must be metabolically activated before functioning biochemically in its target tissues, including the intestine, bone and kidney. The dihydroxylated metabolite of vitamin D.sub.3, namely 1,25(OH).sub.2 D.sub.3, was believed to be responsible for all the known biological functions of the vitamin. This compound is produced from cholecalciferol by C-25 hydroxylation in the liver followed by C-1 hydroxylation in the kidney. It was thus understandable why treatment with cholecalciferol was found to be ineffective in metabolic bone diseases, such as renal osteodystrophy, in patients who, owing to chronic kidney failure, are incapable of converting the cholecalciferol prohormone into its aforesaid dihydroxylated metabolite hormone.
The use of 1,25(OH).sub.2 D.sub.3 is now established in the treatment of renal bone diseases. Its administration increases calcium absorption from the gut and consequently, plasma calcium, and suppresses secondary hyperparathyroidism and its skeletal consequences. It also ameliorates osteomalacia in the presence of secondary hyperparathyroidism. The putative roles of 1,25(OH).sub.2 D.sub.3 in the bone are controversial and many of its actions can be accounted for by its effect to increase the ionized fraction of plasma calcium. This therapeutic effect is also the major cause of vitamin D toxicity, namely hypercalcemia. Its use is therefore contraindicated and indeed of limited value in patients with pre-existing hypercalcemia due to aluminum toxicity or tertiary hyperparathyroidism.
The failure of 1,25(OH).sub.2 D.sub.3 to control secondary hyperparathyroidism in many patients on dialysis stimulated the continuing search for more effective therapeutic means. Intravenous administration of 1,25(OH).sub.2 D.sub.3 has been recently reported to be more effective than the same drug administered by the oral route in suppressing secondary hyperparathyroidism (Slatopolsky et al., J. Clin. Invest 74, 2136, 1984). However, it has not solved the problem of secondary hyperparathyroidism in dialysis patients.
1-alpha(OH)D.sub.3 is a synthetic analog of 1,25(OH).sub.2 D.sub.3. It is converted into the latter in the liver by 25-hydroxylation. 1-alpha(OH)D.sub.3 is now also in clinical use for renal osteodystrophy, and its therapeutic effect is equivalent to that of 1,25(OH).sub.2 D.sub.3 apart from small differences in its biological half-life and dose response.
Although the treatment of chronic renal failure (CRF) with either 1,25(OH).sub.2 D.sub.3 or 1-alpha(OH)D.sub.3 proved to be effective in maintaining normal concentrations of calcium and phosphate in the plasma, the beneficial results on the mineralization of bone matrix were highly incomplete and unsatisfactory.
There has been recent interest in other metabolites of vitamin D.sub.3, notably 25(OH)D.sub.3 and 24,25(OH).sub.2 D.sub.3 which may have different actions on target tissue than 1,25(OH).sub.2 D.sub.3 and 1-alpha(OH)D.sub.3.
Until recently it was still controversial whether 24,25(OH).sub.2 D.sub.3 plays any physiological role in man and in animals, and whether it possesses a defined biological activity. In early observations this metabolite was considered to be only a by-product of renal 25(OH)D.sub.3 metabolism. The uncertainty surrounding the physiological importance of 24,25(OH).sub.2 D.sub.3 stems partially from observations in animals.
In animal experiments, the effect of 24,25(OH).sub.2 D.sub.3 on stimulation of intestinal calcium absorption was contingent upon prior renal hydroxylation to 1,24,25(OH).sub.3 D.sub.3. Thus in nephrectomized animals 24,25(OH).sub.2 D.sub.3 failed to stimulate intestinal transport. Conversely in man where 24,25(OH).sub.2 D.sub.3 has been shown to be active in calcium metabolism 1,24,25(OH).sub.3 D.sub.3 was found to exert only a minimal effect. (Boyle et al., J. Biol. Chem. 248, 4174, 1973).
The increased calcium retention of 24,25(OH).sub.2 D.sub.3 is not associated with hypercalcemia, suggesting that 24,25(OH).sub.2 D.sub.3 may be directly or indirectly promoting calcium uptake in compartments other than the extracellular fluid. There is some evidence that skeletal retention of calcium is augmented. A number of experimental observations in animals suggest that both 1,25(OH).sub.2 D.sub.3 and 24,25(OH).sub.2 D.sub.3 are necessary for some aspects of skeletal metabolism. These include the normal differentiation of cartilage tissue, the healing of fractures and the mineralization of rachitic bone and cartilage and the prevention of parathyroid gland hyperplasia.